The muscular contractions of the four chambers of the heart are mediated by electrical activation that proceeds through the heart in a repeating pattern. Normally, the sinoatrial node initiates each heart-beat cycle by depolarizing so as to generate an action potential. This action potential propagates relatively quickly through the atria, which react by contracting, and then relatively slowly through the atrioventricular node. From the atrioventricular node, activation propagates rapidly through the His-Purkinje system to the ventricles, which react by contracting. The rate at which the sinoatrial node depolarizes determines the rate at which the atria and ventricles contract and thus controls the heart rate. The rate at which the sinoatrial node depolarizes is regulated by the autonomic nervous system which can accelerate the heart rate so that the heart, for instance, beats at a faster rate during exercise and beats at a slower rate during rest. The above-described cycle of events holds true for a healthy heart and is termed normal sinus rhythm.
The heart, however, may have a disorder or disease that results in rapid abnormal activation that preempts sinus rhythm. Atrial fibrillation occurs when the orderly wavefront of activation breaks up into multiple components. Each of these activation wavefronts wanders rapidly and chaotically through the atria. This irregular activation pattern results in uncoordinated and ineffective contraction of the atria as well as a rapid and irregular ventricular rate.
Atrial fibrillation is associated with significant morbidity and mortality. Death rates among atrial fibrillation patients are 20 to 30 percent higher in men and 30 to 50 percent higher in women compared to matched controls. Atrial fibrillation is associated with a more than fourfold increase in risk of stroke and approximately 15 percent of all strokes occur in people with atrial fibrillation. In addition, this arrhythmia has a huge economic impact with heath care costs for these patients ranging from $6,000 to $15,000 per patient per year. Atrial fibrillation is the most common arrhythmia requiring treatment, occurring in about 2 million people in the United States and in about 10% of individuals over 70 years of age. In addition to being aware of the irregular heart activity, people afflicted with atrial fibrillation generally have symptoms of weakness, fatigue, breathlessness and chest pain.
The treatment of atrial fibrillation is difficult since both the natural history of atrial fibrillation and its response to therapy are unpredictable. Presently, arrhythmia duration and echocardiographic measurements of atrial size are used to prognosticate, but give no information regarding the electrophysiologic state of the atria.
Atrial fibrillation is caused by a reentrant mechanism which results in multiple simultaneous reentrant activation wavefronts in the atria. The average size of a reentry pathway for one of these wavefronts during atrial fibrillation is dependent on atrial wavelength, defined as the product of conduction velocity and refractory period. Longer atrial wavelengths are associated with larger and fewer wavefronts while shorter atrial wavelengths result in a greater number of smaller wavefronts. Atrial fibrillation is a progressive disorder and animal and clinical studies have shown an association between shorter wavelengths and persistent atrial fibrillation. The average frequency and degree of fractionation of intra-atrial recordings during atrial fibrillation correlate with wavelength and the size of reentry pathways.
An example of an electrocardiogram (ECG) of normal sinus rhythm is shown in FIG. 1 and is characterized by a P wave, which corresponds with atrial depolarization and contraction of the atria, followed by a QRS complex, which corresponds with depolarization and contraction of the ventricles. Due to size differences between the atria and the ventricles, the P wave is considerably smaller than the QRS complex. A T wave follows the QRS complex and corresponds to ventricular repolarization. Atrial repolarization is difficult to detect with an ECG since the atrial repolarization signal has a small amplitude and is mainly hidden by the much larger QRST complex. In addition to the P wave and the QRST complex, a normal ECG is also characterized by a PR interval, defined as the time between atrial and ventricular contractions, of about 0.12 to 0.20 seconds and regular R-R intervals, defined as the time between QRST complexes, of about 0.60 to 1 second.
In contrast to the normal sinus rhythm of FIG. 1, an example of an ECG for a patient with atrial fibrillation is shown in FIG. 2. As shown in FIG. 2, this ECG lacks P waves and instead has chaotic atrial depolarization manifested as an irregular "fibrillatory" baseline. Atrial fibrillation is also characterized by QRST complexes of a normal shape, due to normal ventricular activation sequence, but with irregular intervals.
Previous attempts to characterize atrial fibrillation based on ECG signals have been unsuccessful. One approach to classifying atrial fibrillation is by the amplitude of the fibrillatory baseline signal. For more than 35 years, coarse atrial fibrillation was thought to be associated with rheumatic mitral valve disease while fine atrial fibrillation was most often seen in patients with ischemic or hypertensive cardiomyopathy. Subsequently, more quantitative studies, however, have failed to show a consistent correlation between a large amplitude "coarse" fibrillatory baseline signal and the presence of rheumatic heart disease or left atrial enlargement. Moreover, fibrillatory baseline amplitude does not appear to be affected by atrial wavelength or to predict the behavior of the arrhythmia. The amplitude of the fibrillatory baseline signal therefore cannot be used to classify the atrial fibrillation.
Another approach to classifying atrial fibrillation has focused on the morphology of intracardiac electrograms. Wells et. al., in "Characterization of Atrial Fibrillation in Man: Studies Following Open Heart Surgery," Pacing Clin Electrophysiol 1978; 1(4):426-38, disclose the use of a single bipolar atrial electrogram recorded directly from the heart after cardiac surgery to stratify the arrhythmia into four different types. Based on Wells classification, Type I fibrillation had discrete signals with intervening isoelectric intervals, Type II fibrillation had discrete activation without any intervening periods of complete electrical quiescence, Type III fibrillation had no clear isoelectric intervals, and Type IV fibrillation was characterized as alternating between the Type I and Type III fibrillation. The clinical utility of this classification technique, however, is limited by the need for invasive recording.
Another approach to classifying atrial fibrillation is proposed by Konings et al. in "High-Density Mapping of Electrically Induced Atrial Fibrillation in Humans," Circulation 1994; 89:1665-80. Konings et al. disclose the classification of atrial fibrillation in patients with the Wolff-Parkinson-White syndrome undergoing cardiac surgery by using high-density intra-operative mapping of the right atrium free wall. Konings et al. categorized the arrhythmia based on the number and complexity of activation wavefronts within a particular 3.6 cm diameter region of the atrium being studied. This approach, as with the approach of Wells et al., suffers from a disadvantage that it is limited by the need for invasive recording. A further limitation of the assessments based on focal or regional activation patterns was shown by Li et. al. in "Distribution of Atrial Electrogram Types During Atrial Fibrillation: Effect of Rapid Atrial Pacing and Intercaval Junction Ablation," J Am Coll Cardiol 1996; 27:1713-21. Li et al. noted that all four patterns of atrial fibrillation described by Wells et. al. were present concurrently at different locations of the atria during experimental atrial fibrillation. The utility of the mapping proposed by Konings et al. is therefore doubtful.
A different approach to the classification of atrial fibrillation has focused on atrial wavelength and fibrillation frequency. An increasing body of evidence suggests that shorter atrial wavelengths are critically important for the initiation and perpetuation of atrial fibrillation. Wavelength measurements have been shown to be accurate predictors of atrial fibrillation inducibility. The persistence of atrial fibrillation and its response to antiarrhythmic drugs has also been found to be closely correlated with wavelength. Several experimental and clinical studies have shown an association between the frequency of fibrillation recorded on the intracardiac electrogram, the atrial wavelength, and the behavior of the arrhythmia.
For instance, Asano et al., in "On the Mechanism of Termination and Perpetuation of Atrial Fibrillation," Am J Cardiol 1992; 69:1033-8, induced atrial fibrillation with rapid pacing in 30 patients undergoing electrophysiologic study. The mean atrial activation interval recorded in the right atrium was well correlated with atrial wavelength; those patients having spontaneous termination of atrial fibrillation had an average fibrillation frequency of 5.6 Hz, significantly lower than the 6.4 Hz recorded in the group of patients where the arrhythmia persisted.
Boahene et. al., in "Termination of Acute Atrial Fibrillation in the Wolff-Parkinson-White Syndrome by Procainamide and Propafenone: Importance of Atrial Fibrillatory Cycle Length," J Am Coll Cardiol 1990; 16:1408-14, measured fibrillatory cycle length from the high right atrium in 55 patients with the Wolff-Parkinson-White syndrome. Boahene et al. also found that patients with sustained atrial fibrillation had shorter mean atrial activation intervals than did their counterparts with non-sustained atrial fibrillation.
In both experimental models of atrial fibrillation and in clinical studies, persistent rapid atrial rates have been shown to produce a marked, progressive shortening of the atrial refractory period. The decrease in refractoriness is accompanied by a comparable increase in the fibrillation frequency. This electrical remodeling is responsible for the self-perpetuating nature of atrial fibrillation and may play a major role in the natural history of the arrhythmia.
Despite an increase in the number of treatment options, the management of atrial fibrillation remains a trial and error process. The initial goal is to restore sinus rhythm. This so-called cardioversion procedure is usually accomplished though administration of a high voltage shock (about 750 VDC-2000 VDC) via paddles placed on the chest. Last year, the Food and Drug Administration approved ibutilide as an effective alternative to such electrical cardioversion of atrial fibrillation. This potent antiarrhythmic drug is administered intravenously for about 10 to 20 about 20 minutes. This option is attractive because it may obviate the need for general anesthesia and a powerful shock. However, ibutilide is effective in less than about one third of the patients with atrial fibrillation.
Patients with persistent or recurrent atrial fibrillation require chronic therapy of their arrhythmia. Coumadin, an anticoagulant, is usually given to these patients to reduce the risk of stroke. Antiarrhythmic drugs may decrease the frequency and severity of atrial fibrillation episodes, but are incompletely effective and associated with significant side effects, including the possibility of proarrhythmia. When the risks and toxicity of antiarrhythmic drugs outweigh their potential benefit, patients are left in atrial fibrillation and palliated with medications that slow the heart rate.
New, non-pharmacological treatments of atrial fibrillation are in clinical trials. An implanted device, slightly larger than a conventional pacemaker, has been developed that automatically detects and shocks atrial fibrillation back into normal rhythm. Atrial fibrillation is also being treated experimentally with catheter ablation. With this technique, a wire is introduced into the femoral vein and advanced into the atrium. High frequency current is passed through the tip of the wire and is used to cauterize the atria. A series of long "lines" are burned into the atria, dividing it electrically into regions too small to support atrial fibrillation.
Current screening techniques have involved the use of intra-atrial electrograms, catheters, or other invasive techniques. A need therefore exists for a non-invasive assessment of the electrophysiologic state of the atria during atrial fibrillation. A need further exists for a classification of atrial fibrillation that can be performed quickly and accurately. The techniques of the present invention are suitable for the prediction of conversion with ibutilide, for estimation of time to recurrence after cardioversion, and for prediction of response to chronically administered antiarrhythmic drugs. The techniques of the present invention will identify suitable candidates for the implanted atrial defribrillator or for catheter ablation. The techniques of the present invention are also suitable for the prediction of left atrial thrombus and the risk of stroke.
Applicants provide a device for rapidly analyzing the electrical signals from the heart of a patient in atrial fibrillation, with the purpose of assessing the suitability of administering electric shock, or ibutilide, or other treatments.